الشريحة 1

Transcript الشريحة 1

Clinical Pharmacy Chapter One Heart Failure Rowa’ Al-Ramahi

DEFINITION

• Heart failure (HF) is a clinical syndrome caused by the inability of the heart to pump sufficient blood to meet the metabolic needs of the body.

• HF can result from any disorder that reduces ventricular filling (diastolic dysfunction) and/or myocardial contractility (systolic dysfunction).

PATHOPHYSIOLOGY

• Causes of systolic dysfunction (decreased contractility) are reduction in muscle mass (e.g., myocardial infarction [MI]), pressure dilated cardiomyopathies, overload high-output states).

tamponade).

and hypertension.

(e.g., systemic and or ventricular hypertrophy. Ventricular hypertrophy can be caused by pulmonary hypertension, aortic or pulmonic valve stenosis) or volume overload (e.g., valvular regurgitation, shunts, • Causes of diastolic dysfunction (restriction in ventricular filling) are increased ventricular stiffness, ventricular hypertrophy, infiltrative myocardial diseases, myocardial ischemia and infarction, mitral or tricuspid valve stenosis, and pericardial disease (e.g., pericarditis, pericardial • The leading causes of HF are coronary artery disease 3

• As cardiac function decreases after myocardial injury, the heart relies by neurohormones on the following and contribute to disease progression.

compensatory mechanisms: (1) tachycardia and increased contractility through sympathetic nervous system activation; (2) the Frank-Starling mechanism, whereby increased preload increases stroke volume; (3) vasoconstriction; and (4) ventricular hypertrophy and remodeling. Although these compensatory mechanisms initially maintain cardiac function, they are responsible for the symptoms of HF • The neurohormonal model of HF recognizes that an initiating event (e.g., acute MI) leads to decreased cardiac output but that the HF state then becomes a systemic disease whose progression is mediated largely and autocrine/paracrine factors.

These substances include angiotensin II, norepinephrine, aldosterone, tumor necrosis factor natriuretic peptides, arginine vasopressin, proinflammatory cytokines (e.g., α, interleukin-6 and interleukin-1β), and endothelin-1.

• Common precipitating factors that may cause a previously compensated patient to decompensate include noncompliance with diet or drug therapy, coronary infections, and anemia.

the sodium ischemia, cardiac events (e.g., MI, atrial fibrillation), pulmonary • Drugs may precipitate or exacerbate HF because of their negative inotropic, cardiotoxic, or sodium- and water retaining properties. They include: Nonselective blockers, calcium channel blockers (CCB), most notably verapamil, various antiarrhythmic agents, especially disopyramide, quinidine, and other class IA drugs; and anthracycline (daunomycin and doxorubicin), the amphetamine-like drugs and cocaine. Examples of drugs that induce and water inappropriate cancer retention pioglitazone and rosiglitazone.

medication chemotherapeutic are NSAID use, β agents (via prostaglandin inhibition), certain antihypertensive drugs, glucocorticoids, androgens, estrogens, and licorice, 5

CLINICAL PRESENTATION

• The patient presentation may range from asymptomatic to cardiogenic shock. The primary symptoms are dyspnea (particularly on exertion) and fatigue, which lead to exercise intolerance. Other pulmonary symptoms include orthopnea, tachypnea, and cough.

paroxysmal nocturnal dyspnea, • Fluid overload can result in pulmonary congestion and peripheral edema.

• Nonspecific symptoms may include fatigue, nocturia, hemoptysis, abdominal pain, anorexia, nausea, bloating, ascites, poor appetite, ascites, mental status changes, and weight gain.

• Laboratory tests for identifying disorders that may cause or worsen HF include compete blood count; serum electrolytes (including calcium and magnesium); renal, hepatic, and thyroid function tests; urinalysis; lipid profile; and hemoglobin A1C.

• Ventricular hypertrophy can be demonstrated on chest x ray or ECG. Chest x-ray may also show pleural effusions or pulmonary edema.

• The echocardiogram is the single most useful evaluation procedure because it can identify abnormalities of the pericardium, myocardium, or heart values and quantify the left ventricular ejection fraction (LVEF) to determine if systolic or diastolic dysfunction is present.

• The New

symptomatic

York Heart activity without discomfort.

Association HF patients according to the Functional Classification System is intended primarily to classify physician’s subjective evaluation. Functional class (FC)-I patients have no limitation of physical activity, FC-II patients have slight limitation, FC-III patients have marked limitation, and FC-IV patients are unable to carry on physical 7

DESIRED OUTCOME

The therapeutic goals for chronic HF are to: 1.

improve quality of life relieve or reduce symptoms prevent or minimize hospitalizations slow disease progression and prolong survival

.

TREATMENT OF CHRONIC HEART FAILURE

• GENERAL APPROACH • The first step in managing chronic HF is to determine the etiology or precipitating factors. Treatment of underlying disorders (e.g., anemia, hyperthyroidism) may obviate the need for treating HF.

• Nonpharmacologic rehabilitation and restriction of fluid intake (maximum 2 L/day from all interventions sources) and include dietary cardiac sodium (approximately 2 to 3 g of sodium per day).

• •

Stage A

(Patients at high risk for developing HF): The emphasis is on identifying and modifying risk factors to prevent development of structural heart disease and subsequent HF. Strategies include smoking cessation and control of hypertension, diabetes mellitus, and dyslipidemia according to current treatment guidelines.

Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers [ARBs])

strongly considered for antihypertensive therapy in patients with multiple vascular risk factors.

should be

Stage B:

but no symptoms, treatment is targeted at minimizing additional In these patients with structural heart disease injury receive both and preventing remodeling process. In addition to treatment measures outlined for stage A, patients with a previous MI should

ACE inhibitors

(or or

ARBs

slowing the in patients intolerant of ACE inhibitors) and β

- blockers

regardless of the ejection fraction. Patients with reduced ejection fractions (less than 40%) should also receive both agents, regardless of whether they have had an MI.

• •

Stage C:

Most patients with structural heart disease and previous or current HF symptoms should receive the treatments for Stages A and B as well as initiation and titration of a

diuretic

(if clinical evidence of fluid retention), β

-blocker ACE inhibitor

improve once , and (if not already receiving a β- blocker for previous MI, left ventricular [LV] dysfunction, or other indication). If diuresis is initiated and symptoms the patient is euvolemic, monitoring can begin. If symptoms do not improve, an

aldosterone receptor antagonist, ARB

long-term (in ACE inhibitor intolerant patients),

digoxin

, and/or

hydralazine/isosorbide dinitrate

carefully selected patients. Other general measures include moderate sodium (ISDN) may be useful in restriction, daily weight measurement, immunization against pneumococcus, modest physical activity, and avoidance of medications that can exacerbate HF.

influenza and

Stage D:

medical therapy should be considered for specialized therapies, Patients with symptoms at rest despite maximal including mechanical circulatory support, continuous intravenous positive inotropic therapy, cardiac transplantation, or hospice care.

Drug Therapies for Routine Use

1. Diuretics

• Compensatory mechanisms in HF stimulate excessive sodium and water retention, often leading to systemic and pulmonary congestion.

Consequently, diuretic therapy recommended in all patients with clinical evidence of fluid retention. However, because they do not alter disease progression or prolong survival, they are not considered mandatory therapy for patients without fluid retention.

(in addition • Thiazide diuretics (e.g.,

metolazone

to sodium restriction)

hydrochlorothiazide

) is are relatively weak diuretics and are used alone infrequently in HF. However, thiazides or the thiazidelike diuretic can be used in combination with a loop diuretic to promote effective diuresis. Thiazides may be preferred over loop diuretics in patients with only mild fluid retention and elevated blood pressure because of their more persistent antihypertensive effects.

• Loop diuretics (

furosemide, bumetanide, torsemide

) are usually necessary to restore and maintain euvolemia in HF. In addition to acting in the thick ascending limb of the loop of Henle, they induce a prostaglandin-mediated increase in renal blood flow that contributes to their natriuretic effect.

• Unlike be used thiazides, for loop additional diuretics although higher doses may be necessary.

effect, maintain their effectiveness in the presence of impaired renal function, • Doses of loop diuretics above the recommended ceiling doses produce no additional diuresis in HF. Thus, once those doses are reached, more frequent dosing should rather than giving progressively higher doses.

2. Angiotensin-Converting Enzyme Inhibitors

• ACE inhibitors decrease angiotensin II and aldosterone, attenuating many of their deleterious effects, including reducing ventricular remodeling, myocardial fibrosis, myocyte apoptosis, cardiac hypertrophy, norepinephrine release, vasoconstriction, and sodium and water retention. Clinical trials have produced unequivocal evidence that ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in patients with HF and reduced LVEF (stage C). These patients should receive ACE inhibitors unless contraindications are present. ACE inhibitors should also be used to prevent the development of HF in at-risk patients (i.e., stages A and B).

. β

-Blockers

• There is overwhelming clinical trial evidence that certain β-blockers remodeling, slow disease decreasing inhibiting plasma renin release.

progression, decrease hospitalizations, and reduce mortality in patients with HF.

• Beneficial effects of β-blockers may result from antiarrhythmic effects, slowing or reversing ventricular myocyte death from catecholamine-induced necrosis or apoptosis, preventing fetal gene expression, improving LV systolic function, decreasing heart rate and ventricular wall stress and thereby reducing myocardial oxygen demand, and • The ACC/AHA guidelines recommend use of β-blockers in all stable patients with HF and a reduced LVEF in the absence of contraindications or a clear history of β blocker intolerance. Patients should receive a even if symptoms are mild or well controlled with ACE inhibitor and diuretic therapy.

β- blocker 15

• It is not essential that ACE inhibitor doses be optimized before a β-blocker is started because the addition of a β blocker is likely to be of greater benefit than an increase in ACE inhibitor dose.

• β-Blockers are also recommended for asymptomatic patients with a reduced LVEF (stage B) to decrease the risk of progression to HF.

• Because of their negative inotropic effects, β-blockers should be started in very low doses with slow upward dose titration to avoid symptomatic worsening or acute decompensation. Patients should be titrated to target doses when possible to provide maximal survival benefits. However, even lower doses have benefits over placebo, so any dose is likely to provide some benefit.

• Metoprolol CR/XL, carvedilol, and bisoprolol are the only β-blockers shown to reduce mortality in large HF trials. It cannot be assumed that immediate-release metoprolol will provide benefits equivalent to metoprolol CR/XL.

Because bisoprolol is not available in the necessary starting dose of 1.25 mg, the choice is typically limited to either carvedilol or metoprolol CR/XL.

• Doses should be doubled no more often than every 2 weeks, as tolerated, until the target dose or the maximally tolerated dose is reached. Patients should understand that dose up-titration is a long, gradual process and that achieving the target dose is important to maximize benefits. Further, the response to therapy may be delayed, and HF symptoms may actually worsen during the initiation period.

Drug Therapies to Consider for Selected Patients

1 . Angiotensin II Receptor Blockers

• The angiotensin II receptor antagonists block the angiotensin II receptor subtype AT1, preventing the deleterious effects of angiotensin II, regardless of its origin.

They do not appear to affect bradykinin and are not associated with the side effect of cough that sometimes results from ACE inhibitor unopposed stimulation of – induced accumulation of bradykinin. Also, direct blockade of AT1 receptors allows AT2 receptors, causing vasodilation and inhibition of ventricular remodeling.

• Although some data suggest that ARBs produce equivalent mortality benefits when compared to ACE inhibitors, the ACC/AHA guidelines recommend use of ARBs only in patients with stage A, B, or C HF who are intolerant of ACE inhibitors. Although there are seven ARBs on the market in the United States, only candesartan and valsartan are FDA-approved for the treatment of HF and are the preferred agents.

• Blood pressure, renal function, and serum potassium should be evaluated within 1 to 2 weeks after therapy initiation and dose increases, with these endpoints used to guide subsequent dose changes. It is not necessary to reach target ARB doses before adding a • Cough and angioedema are the most common causes of ACE inhibitor intolerance. Caution should be exercised when ARBs are used in patients with angioedema from ACE inhibitors because reported. ARBs are not alternatives in patients with hypotension, hyperkalemia, or renal insufficiency due to ACE inhibitors because they are just as likely to cause these adverse effects.

cross-reactivity • Combination therapy with an ARB and ACE inhibitor offers a theoretical advantage over either agent alone through more complete blockade of the deleterious effects of angiotensin II. However, clinical trial results indicate that the addition of an ARB to optimal HF therapy offers marginal benefits at best with increased risk of adverse effects. Addition of an ARB may be considered in patients who remain symptomatic despite receiving optimal conventional therapy β-blocker.

has been 19

•

Aldosterone Antagonists

Spironolactone

and

eplerenone

block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion.

However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other actions.

Effects in the heart attenuate cardiac fibrosis and ventricular remodeling. Recent evidence also suggests an and important role progesterone in attenuating the systemic proinflammatory state and oxidative stress caused by aldosterone. Spironolactone also interacts with androgen receptors, which gynecomastia and other sexual side effects; these effects are less frequent with eplerenone because of its low affinity for androgen and progesterone receptors.

Based on clinical trial results demonstrating reduced mortality, low-dose aldosterone antagonists may be appropriate for: (1) patients with moderately severe to severe HF who are receiving standard therapy; and (2) those with LV dysfunction early after MI.

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• Data from clinical practice suggest that the risks of serious hyperkalemia and worsening renal function are much higher than observed in clinical trials. This may be due in part to failure of clinicians to consider renal impairment, reduce or stop potassium supplementation, or monitor renal function and potassium closely once the aldosterone antagonist is initiated. Thus, aldosterone antagonists must be used cautiously and with careful monitoring hyperkalemia.

of renal function and potassium concentration. They should be avoided in patients with renal impairment, recent worsening of renal function, high-normal potassium levels, or a history of severe 21

3. Digoxin

• Although digoxin has positive inotropic effects, its benefits in HF are related to its neurohormonal effects. Digoxin attenuates the excessive sympathetic nervous system activation present in HF patients, perhaps by reducing central benefits.

sympathetic outflow and improving impaired baroreceptor function. It also increases parasympathetic activity in HF patients and decreases heart rate, thus enhancing diastolic filling. Digoxin does not improve survival in patients with HF but does provide symptomatic • In patients with HF and supraventricular tachyarrhythmias such as atrial fibrillation, digoxin should be considered early in therapy to help control ventricular response rate.

• For patients in normal sinus rhythm, effects on symptom reduction and quality-of-life improvement are evident in patients with mild to severe HF. Therefore, it should be used together with standard HF therapies (ACE inhibitors, β-blockers, and diuretics) in patients with symptomatic HF to reduce hospitalizations.

• Doses should be adjusted to achieve plasma digoxin concentration of 0.5 to 1 ng/mL. Higher plasma levels are not associated with additional benefits but may increase the risk of toxicity. Most patients with normal renal function can achieve this level with a dose of 0.125

mg/day. Patients with decreased renal function, the elderly, or those receiving interacting drugs (e.g., amiodarone) should receive 0.125 mg every other day.

In the absence of supraventricular tachyarrhythmias, a loading dose is not indicated because digoxin is a mild inotropic agent that produces gradual effects over several hours, even after loading. Blood samples for measuring plasma digoxin concentrations should be collected at least 6 hours, and preferably 12 hours or more, after the last dose.

4. Nitrates and Hydralazine

• Nitrates (e.g., originally in the treatment of HF because of their complementary primarily venodilators, producing reductions in preload.

Hydralazine combination

ISDN

is hemodynamic predominantly on arterial smooth muscle to reduce systemic vascular resistance and increase stroke volume and cardiac output. Evidence also suggests that the may with HF progression.

standard therapy a ) and

hydralazine

direct provide actions.

were combined vasodilator additional Nitrates that benefits are acts by interfering with the biochemical processes associated • The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive 24

• Practice guidelines recommend adding ISDN and hydralazine as part of standard therapy in African Americans with moderately severe to severe HF. The combination may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor (or ARB) and β-blocker.

The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension.

• Obstacles to successful therapy with this drug combination include the need for frequent dosing (i.e., three times daily with the fixed-dose combination product), a high frequency of adverse effects (e.g., headache, dizziness, GI distress), and increased cost for the fixed-dose combination product.

TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE

• GENERAL APPROACH • The term

decompensated HF

refers to patients with new or worsening signs or symptoms that are usually caused by volume overload and/or hypoperfusion and lead to the need for additional medical care, such as emergency department visits and hospitalizations.

• The goals of therapy are to relieve congestive symptoms, optimize volume status, treat symptoms of low cardiac output, and minimize the risks of drug therapy so the patient can be discharged compensated state on oral drug therapy.

in a 26

• Reversible or treatable causes of decompensation should be addressed and corrected. Drugs that may aggravate HF should be evaluated carefully and discontinued when possible.

• The first step in managing decompensated HF is to ascertain that optimal treatment with oral medications has been achieved. If there is evidence of fluid retention, aggressive diuresis, often with IV diuretics, should be accomplished. Optimal treatment with an ACE inhibitor should be a priority. Although β-blockers should not be started during this period of instability, they should be continued, if possible, in patients who are already receiving them on a chronic basis. Most patients should be receiving digoxin at a low dose prescribed to achieve a trough serum concentration of 0.5 to 1 ng/mL.

Treatment

• •

Diuretics:

IV loop diuretics, including

furosemide, bumetanide,

and

torsemide

, are used for acute decompensated HF, with furosemide being the most widely studied and used agent.

Positive Inotropic Agents

–

Dobutamine

– –

Milrinone Dopamine

•

Vasodilators

–

Nitroprusside

–

Nitroglycerin

–

Nesiritide

MECHANICAL CIRCULATORY SUPPORT

Intraaortic Balloon Pump Ventricular Assist Devices

SURGICAL THERAPY 28

EVALUATION OF THERAPEUTIC OUTCOMES

1. Patients should be asked about the presence and severity of symptoms and how the symptoms affect their daily activities.

2. The efficacy retention.

of diuretic treatment is evaluated by disappearance of the signs and symptoms of excess fluid 3. Other outcomes include improvement in exercise tolerance and fatigue, decreased nocturia, and a decrease in heart rate.

4. Blood pressure should be monitored symptomatic hypotension does not develop as a result of drug therapy.

to ensure that 5. Body weight is a sensitive marker of fluid loss or retention, and patients should weigh themselves daily.

6. Symptoms may worsen initially on may take weeks to symptomatic improvement.

months β-blocker therapy, and it before patients notice 7. Routine monitoring of serum electrolytes and renal function is mandatory in patients with HF.